BRPI0506970B1 - alpha-aminoamide derivatives useful in treating lower urinary tract disorders - Google Patents

Abstract

alpha-aminoamide derivatives useful in the treatment of lower urinary tract disorders. The present invention relates to methods for using certain β-aminoamide derivatives to treat lower urinary tract disorders. The therapeutic agents of the invention are capable of reducing or even interrupting lower urinary tract disorders without side effects.

Description

The present invention relates to new and known α-aminoamide derivatives, a chemical class of sodium channel blockers, and their use in the treatment of lower urinary tract disorders and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Lower urinary tract disorders (LUT), which affect the quality of life of millions of people worldwide each year, include, but are not limited to, overactive bladder (OAB), prostatitis and prostadena, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence.

/ * OAB is the most common term currently used in medicine. ’· * 15 clinic to describe a complex of lower urinary tract symptoms,» with or without incontinence. Symptoms usually include urgency, frequency, nocturia, disturbing or incomplete emptying and, occasionally, pain. The causes of bladder overactivity include neurological disease or lust, obstruction of the bladder, urethral weakness, detrusor hyperactivity • 20 and deteriorated contractility in elderly patients, the emergence of new elimination reflexes and the so-called idiopathic bladder overactivity. Neurogenic overactive bladder occurs as a result of • neurological damage, due to disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy or spinal cord injuries. In contrast, non-neurogenic OAB can result from non-neurological abnormalities, including bladder stones, muscle disease, urinary tract infection, or drug side effects. OAB can result from hypersensitivity of sensory neurons in the urinary bladder, resulting from several factors, including inflammatory conditions, hormonal imbalances and prostate hypertrophy.

Prostatitis is a term to describe inflammatory conditions in the prostate gland. It is thought that most cases of prostate cancer2

result from bacterial infection, but evidence of infection is not always found. An infected or inflamed prostate can cause painful urination with serious complications. There are four types of prostatitis: acute bacteratan prostatitis, chronic bactertan prostatitis, non-bactertan prostatitis and 5 prostaden, also called chronic pelvic pain syndrome, which is a condition associated with painful symptoms of chronic non-bacterial prostatitis, without an inflammation of the prostate.

Interstitial cystitis (HF) is a chronic inflammatory condition of the bladder, which causes frequent, urgent and painful urination and pelvic discomfort. Unlike common cystitis (inflammation of the bladder caused by bacterial infection), no infectious agent was found in HF.

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate, which is very common in men over 40 years of age. The prostate grows in two different ways. In a type of growth, the cells 15 multiply around the urethra, in a second, the growth of the cells is in the direction of the urethra and the exit area of the bladder. This second type of growth typically requires surgery. Common symptoms of BPH include: blood in the urine, feeling that the bladder has not been emptied completely after urination, frequent urination, nocturia, urgent need to urinate and incontinence. In severe cases of BPH, another symptom is acute urinary retention.

The function of the LUT is to store and release urine periodically. This requires the orchestration of storage and urination reflexes involving both the sympathetic and parasympathetic components of the autonomic nervous system and motor pathways.

Urinary incontinence (IU) occurs when the lower urinary tract does not store urine properly and there is an involuntary loss of urine. There are 3 types of UI: impulsive, tension and mixed. The impulsive UI is considered to be due to an overactive bladder, while the tension UI is considered to be due to less resistance to urethral discharge. The mixed UI contains both components. Symptoms are: urinary frequency, urgency, nocturia and accidental loss of urine. When the

·· conscious control of the parasympathetic urination reflex is compromised, OAB and / or UI conditions appear, creating serious health and social concerns.

Drugs that eliminate the urination reflex can be useful for the treatment of OAB and UI. One of the targets for eliminating OAB consists of the primary afferent neurons and their peripheral terminals in the bladder. Therapeutic agents that eliminate the initiation and / or potential propagation along the primary afferent fibers, through modulation of tonic channels, are expected to increase the volumetric limit for activation of the urination reflex and, thus, reduce the overactivity and urgency of urine.

Current treatments for OAB include antimuscarinic drugs, changes in diet, urine training programs, electrical stimulation and surgery.

Currently, there are no established treatments for prostatitis and prostadena. Antibiotics, COX-2 inhibitors and aadrenergic blockers are often prescribed, but their effectiveness has not been established.

Treatments for GI, which include administration of anti20 histamines, poly pentosan (sodium sulfate), dimethyl sulfoxide, tricyclic antidepressant steroids and narcotic antagonists have generally been unsuccessful.

Non-invasive treatments for BHP include androgen deprivation therapy and the use of 5a-reductase inhibitors and a25 adrenergic blockers with minimal efficiency.

Because existing therapies and treatments for LUT disorders are associated with limitations, as described above, different therapies and treatments are desirable.

However, despite the large number of therapeutic agents available, their use suffers from limited efficiency and side effects, such as dry mouth, dry eyes, dry vagina, palpitations, changes in heart rate, drowsiness, mental confusion, particularly in people

II

• ♦ * ··· #

elderly women, and constipation, which proved to be difficult for individuals to tolerate.

Since the sensory afferent neurons, expressing sodium channels, are hypersensitized in bladder dysfunction, it seems. It is reasonable to consider that blocking sodium channel activity may represent a new strategy for the treatment of disorders of the lower urinary tract.

The present invention provides fast and highly effective methods for treating a variety of lower urinary tract disorders by using, in vivo, certain compounds of the a10 aminoamide invention in a therapy, as an alternative to existing treatments.

International patent applications WO 90/14334, WO 94/22808, WO 97/05102, WO 97/0511 and WO 99/35125, the texts of which are incorporated herein by reference, describe substituted benzylaminopropio15 compounds active in the central nervous system and useful as antiepileptic, antiparkinson, neuroprotective, antidepressant and antispathic hypnotics (see also Pevarello P. et al. (1998), Synthesis and anticonvulsant activity of a new class of 2 - [(arylalkyl) amino] alkanamide derivatives, J. Med. Chemistry, 41: 597 - 590). International patent applications WO 99/35125 and WO 99/35123 describe substituted benzylaminopropanamide compounds active in the central nervous system and useful as analgesic agents (see also Veneroni O. et al. (2003) Antiallodynic effect of NW-1029, a novel Na ⁺ channel blocker, in experimental animal models of inflammatory and neuropatic pain, Pain 102 (1-2): 17 - 25).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the use of the compounds of formula I for the preparation of a drug for the treatment of lower urinary tract disorders. The compounds according to the invention are derived from the aminoamide of formula (I):

1L

R (CH ₂ Uh>

^{CH 2 ⁾ 1UY ~ ^CR ACONR4R ₅

R.

(I) * * in which:

- R is a furyl, phenyl or pyridyl ring, or a phenyl ring optionally substituted by one or two substituents selected independently from halogen, hydroxy, cyano, Ct - C ₆ alkyl, C ₁ - C ₆ alkoxy or trifluoromethyl;

- R-ι is hydrogen or C ₄ - Cg alkyl or C ₃ - C ₇ cycloalkyl;

- R ₂ and R ₃ are independently selected from hydrogen, Ci - C ₄ alkyl optionally substituted by hydroxy or phenyl, phenyl, the phenyl rings being optionally substituted by one or two substituents * 10 selected independently from Ct - C ₆ alkyl, halogen , hydroxy, Ct C ₆ alkoxy or trifluoromethyl; or R ₂ and R ₃ , considered with the carbo 'atom to which they are attached, form a ring of C ₃ - C _and cycloalkyl;

- R ₄ and R _s are, independently, hydrogen, C 1 - C ₆ alkyl or C ₃ - O? cycloalkyl; or R <and Rs, taken together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring of 5 to 7 atoms;

. -XéOfe, OouS;

- Y and Z are hydrogen or taken together form a saturated or unsaturated carbocycle or heterocycle;

or pharmaceutically acceptable isomers, mixtures and salts thereof.

The alkyl and alkoxy groups can be branched or linear.

Pharmaceutically acceptable salts of the compounds of the invention include, for example, acid addition salts with inorganic acids, for example, nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like, or organic acids, for example, acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, damic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic, and similar.

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• * <· • »· • ·; · ··

Some of the compounds of formula (I) may have asymmetric carbon atoms and, therefore, may exist as racemic mixtures or as individual optical isomers (enantiomers). Accordingly, the term pharmaceutically acceptable salts of the α-aminoamide of formula (I) is also mentioned as including within its scope all possible isomers and mixtures thereof, and any pharmaceutically acceptable metabolites, bioprecursors and / or prodrugs, i.e. , a compound that has a structural formula different from that of the α-aminoamide of formula (I) and is further converted, directly or indirectly, in vivo, into a compound having formula (I), upon administration to a mammal, particularly a being human.

X and Y are in a meta or a reciprocal position.

The compounds of formula (I), in which Y together with Z form a dihydrobenzofuran or dihydrobenzothiophene heterocycle or a dihydrobenzo (thio) pyran or a tetrahydrobenzo (thio) oxepine, are different and are another object of the invention.

Preferably, in the compounds of formula I:

- R is a phenyl ring, optionally substituted by one or two substituents selected independently from a halogen, trifluoromethyl, a methoxy, or a thienyl ring;

- Ri is hydrogen or C-ι - C ₄ alkyl;

- one of R ₂ and R ₃ is hydrogen and the other is Ci - C ₄ alkyl, optionally substituted by hydroxy or phenyl, optionally substituted by one or two halogen atoms, or R ₂ and R ₃ are both methyl or form together with the atom to which a cyclopropyl or cyclopentyl ring is attached; and

- R ₄ and Rs are hydrogen or C ₃ - C ₄ alkyl, or together with the nitrogen atom to which they are attached, form a pyrrolidine or piperidine ring, and their pharmaceutically acceptable salts.

Examples of compounds for use according to the invention

include:

2- (4-Phenethylbenzylamino) -propanamide;

. 2- (4-Benzyloxybenzylamino) -propanamide;

. 2- (3-Benzyloxybenzylamino) -propanamide;

2- (4-Benzylthiobenzylamino) -propanamide;

2- (4-Benzyloxybenzylamino) -3-N, N-dimethylbutanamide;

2- [4- (2-Methoxybenzyloxy) -benzylamino] -propanamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -propanamide;

2- [3- (2-Fluorobenzyloxy) -benzylamino] -propanamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -propanamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -2-methylpropanamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -N-methylpropanamide;

2- (3- (3-Fluorobenzyloxy) -benzylamino] -propanamide;

2- (4- (3-Fluorobenzyloxy) -benzylamino] -propanamide;

2- [4- (3-Methoxybenzyloxy) -benzylamino] -propanamide;

2- [4- (3-Cyanobenzyloxy) -benzylamino] -propanamide;

2- (4- (3-Fluorobenzyloxy) -benzylamino] -propanamide;

2- (4- (3-Fluorobenzyloxy) -benzylamino] -2-methylpropanamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -N-methanolpropanamide;

2- [4- (4-Fluorobenzyloxy) -benzylamino] -propanamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -2-methylpropanamide;

2- [4- (2-Chlorobenzyloxy) -benzylamino] -propanamide;

2- (4- (3-Chlorobenzyloxy) -benzylamino] -propanamide;

2- (4-Benzyloxybenzylamino) -3-hydroxypropanamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -3-hydroxypropanamide;

2- (4- (3-Fluorobenzyloxy) -benzylamino] -3-hydroxypropanamide;

2- (4-Benzyloxybenzi) amino) -3-hydroxy-N-methylpropanamide; 2- [4- (2-Fluorobenzyloxy) -benzifamino] -3-hydroxy-Nmethylpropanamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -3-hydroxy-Nmethylpropanamide;

2- [4- (2-Chlorobenzyloxy) -benzylamino] -3-hydroxy-N-

·· * ··· ·· • · ·· • ·· · • · «· · • · * • · • • · «* ··· ♦ · • • · • · · • 9 »· »* · «* · · * · • · » ♦ • * · ♦ * · • • ·

methylpropanamide;

2- [4- (3-Cyanobenzyloxy) -benzylamino] -3-hydroxy-Nmethylpropanamide;

2- [4- (3-Cyanobenzyloxy) -benzylamino] -2-methyl-3-hydroxy-N5 methylpropanamide;

2- [4- (3-Chlorobenzyloxy) -phenylethylamino] -propanamide;

2- {4- [2- (3-Fluorophenyl) -ethyloxy] -benzylamino} -propanamide;

2- {4- [2- (3-Fluorophenyl) -ethyl] -benzylamino} -propanamide;

2- [N- (4-Benzyloxybenzyl) -N-methylamino] -propanamide;

2- {4 - [(3-Chlorobenzyloxy) -phenylethyl] -amino} -propanamide;

2- [4-Benzylthiobenzylamino] -propanamide;

2- [4- (2-Fluorobenzylthio) -benzylamino] -propanamide;

2- [4- (3-Fluorobenzylthio) -benzylamino] -propanamide;

2- [4- (3-Phenylpropyloxy) -benzylammon] -propanamide;

2- [4- (4-Phenylbutyloxy) -benzylamino] -propanamide;

2- [4- (5-Phenylpentyloxy) -benzylamino] -propanamide;

2- (4-Benzyloxybenzylamino) -3-phenyl-N-methylpropanamide;

2- (4-Benzyloxybenzylamino) -3-hydroxy-N-methylbiitanamide;

2- (4-Benzyloxybenzylamino) -3-methyl-N-methylbutanamide;

2- (4-Benzyloxybenzylamino) -2-phenylacetamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -2-phenylacetamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -2-phenylacetamide;

2- [4- (2-Fluorobenzyloxy) -benzii-N-methylamino] -2-phenylacetamide;

2- [4- (3-Fluorobenzyloxy) -benzyl-N-methylamino] -2-phenylacetamide;

2- [4- (3-Chlorobenzyloxy) -benzylamino] -2-phenylacetamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -2- (2-fluorophenyl) -acetamide;

2- [4- (2-Fluorobenzyloxy) -benzylamino] -2- (3-fluorophenyl) -acetamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -2- (2-fluorophenyl) -acetamide;

2- [4- (3-Fluorobenzyloxy) -benzylamino] -2- (3-fluorophenyl) -acetamide;

2- [4- (3-Chlorobenzyloxy) -benzylamino] -2- (3-fluorophenyl) -acetamide;

and

2- (4- (2-Thienyloxy) -benzylamino) -propanamide.

• · · • · · * · · • * » · · • * · ·· · «. ** • · · • · 9 · is " · *· «· · • • ·· · · * · · and * «·· · • · · · w · • « «« · «« · * · «* · «·« ♦ ·

IB

Examples of other compounds of formula (I) include:

2 - [(3'Benzyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] - propanamide;

* 2 - [(3-Benzyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -N-. methylpropanamide;

(2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) - * propanamide;

2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) N-methylpropanamide;

2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) 10 propanamide;

2-3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) -Nmethylpropanamide;

2 - [(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -aminoJ-propanami • t da;

. 15 2 - [(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -Nmethylpropanamide;

2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) 20 N-methylpropanamide;

2-3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2- {3- [2- (3-Chlorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} - amino) propanamide;

2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-itmethylamino) -Nomethylpropanamide;

2 - [(3-Phenethyl-2,3-dihydrobenzopyran-6-ylmethyl) -amino] -propanamide;

2 - [(4-Phenethyl-2,3-dihydrobenzoxepin-7-ylmethyl) -amino] - propanamide;

2 - [(3-Benzyl-2,3-dihydrobenzothiophen-5-ylmethyl) -amino] - propanamide;

2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) 10 ...

»· • ♦ • ·· *

«« · «·· ·· • · ·· ·» «» »» ·> · «» «• ♦ · · ·» »·· propanamide;

2- {3- [2- (3-FkJorobenzyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) • propanamide;

- 2 - [(3-Phenethyl-2,3-dihydrobenzothiophen-5-ylmethyl) -aminoJ5 propanamide;

2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide;

2- (3- (2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl) -amino) propanamide; and

2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) N-methylpropanamide, or pharmaceutically acceptable isomers, mixtures and salts thereof.

Preferred compounds of formula (I), which can be used alone or in combination with other compounds of formula (I) are: (S) (+) - 2- [3- (2-fluorobenzyloxy) -benzylamino] -propanamide, (S) - (+) - 2- [4- (2-fluorobenzyloxy) -benzylamino] -propanamide (NW-1029), (S) - (+) - 2- [4- (2-fluorobenzyloxy) -benzylamino] -N-methylpropanamide, (SX +) - 2- [3- (3-fluorobenzyloxy) -benzylaminoj-propanamide, (S) - (+) - 2- [4- (3-fluorobenzyloxy) -benzylamino] -propane20 mida (R ) -2- (4-benzyloxybenzylamino) -3-phenyl-N-methylpropanamide, (2R, 3S) -2 (4-benzyloxybenzylamino) -3-hydroxy-N-methylbutanamide, (S) - (+) - 2- [ 4- (3-fluorobenzyloxy) -benzylamino] -N-methylpropanamide, (S) - (+) - 2- (4-phenethylbenzylamino) propanamide, (R) - (-) - 2- (4-benzyloxybenzylamino) -3- N, N-dimethylbutanamide, (S) - (+) - 2- (4-benzylthiobenztlamino) -propanamide, 2 - [(3-phenethyl-2,3-dihydro25 benzofuran-5-ylmethyl) -amino] -N-methylpropanamide , and (2R / 3'S, R) -2 - [(3-phenethyl2,3-dihydrobenzofuran-5-ylmethyl) -amino] -N-methylpropanamide, 2- {3- [2- (2-fluorophenethyl)] - 2 , 3-dihydrobenzothiof en-5-ylmethyl} -amino) -propanamide, 2- (3- (2- (3fluorophenethyl)] - 2,3-dihydrobenzothiofen-5-ylmethyl} -amino) -propanamide, (2R / 3'S, R) -2- {3- [2- (2-fluorophenethyl) -2,3-dihydrobenzothiophen-5-ylmethyl} -amino) 30 propanamide and (2R / 3'S, R) -2- {3- [2- (3- fluorophenethyl) -2,3-dihydrobenzothiophen-5ylmethyl} -amino) -propanamide.

The preparation of the known compounds of formula I is described in international patent applications WO 90/14334, WO 94/22808, WO 97/05102, WO 97/0511, WO 99/35125 and WO 99/35123.

• The preparation of the compounds can be carried out by reaction of. an ester of 4-hydroxy-3-iodobenzoic acid with the substituted 4-phenylbut-25yl bromides or suitable substituted ethyl cinnamyl bromides, in the presence of bases (eg NaH) and a suitable catalyst, such as crown ether .

The 3-iodo-4 - {[(2E) -4-phenyl-but-2-enyl] -oxy} benzoate or the 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate esters are then transformed into the corresponding 3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-carboxylates or 3-benzyl-2,310 dihydro-1-benzofuran-5-carboxylates in the presence of AIBN and hydride of tributyltin. The reduction by known processes of 5-carboxylate groups to 5-hydroxymethyl groups, followed by oxidation to 5-carboxaldehyde groups, provides intermediate compounds which, by reducing amination with an amine of the formula NHRr 15 CR2R3CONR4R5. wherein R1-R5 have the same meanings as indicated above, produce the desired benzofuran derivatives. Similarly, starting from esters of 4-mercapto-3-iodobenzoic acid, the corresponding benzothiophene derivatives can be obtained.

In one embodiment, the patient being treated is a mammal, including humans, in need of relief, prevention or inhibition of symptoms of lower urinary tract disorders.

In particular, the mammal in need of the treatment mentioned above is administered a dose of an α-aminoamide of formula (I), as defined above, ranging from about 0.3 to about 100 mg / kg of body weight per day . Treatment as used herein includes any care for procedures or applications to a mammal and, particularly, a human being, which are intended to: a) prevent the disease or disorder from occurring in a patient who may be predisposed to the disease / disorder, but who has not yet been diagnosed as having them; b) start the disease / disorder, or condition, that is, interrupting its development; or c) mitigating the disease / disorder, or condition, that is, causing regression of the disease / disorder, or condition.

Lower urinary tract disorders in a mammal, including humans, can thus be inhibited, slowed and prevented.

• Examples of lower urinary tract disorders in mammals, which can. may be treated by administration of one or more a5 aminoamide compounds of formula (I), include, but are not limited to: overactive bladder (OAB), prostatitis and prostadena, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence. In another aspect, the invention includes an aaminoamide of formula (I), administered as the active agent of a pharmaceutically acceptable composition, having activity in lower urinary tract disorders, which can be prepared by conventional procedures known in the art, for example, by mixing the active agent with an organic and / or inorganic carrier or therapeutically inert, pharmaceutically acceptable excipient materials.

Combinatory therapy (or co-therapy) includes the administration of an alpha-aminoamide compound of formula (I) of the invention and at least a second agent, as part of a specific treatment regimen, to provide the beneficial effect of the joint action of these therapeutic agents. The benefits of these combinations include reducing the dose of conventional therapeutic agents (i.e., different from the agents of this invention) with a consequent reduction in the side effects of these conventional agents. The beneficial effect of the combination includes, but is not limited to, joint pharmacokinetic or pharmacodynamic actions resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically conducted for a defined period of time (usually minutes, hours, days or weeks, depending on the combination selected). Combinatorial therapy may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents, as part of separate monotherapeutic regimens, which result, eventually and arbitrarily, in the combinations considered by the present invention. Combinatory therapy is intended to cover the administration of these therapeutic agents in a sequential manner, that is, in which each therapeutic agent is administered at a time

different, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially ♦ simultaneous manner. Substantially simultaneous administration can be made, for example, by administration to the patient of a single capsule, having a fixed ratio of each therapeutic agent or in single, multiple capsules for each of the therapeutic agents. The sequential or substantially simultaneous administration of each therapeutic agent can be done by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes and direct absorption by tissues of mucous membranes. Therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally.

Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The sequence in which therapeutic agents are administered is not strictly critical. Combinatory therapy may also encompass the administration of therapeutic agents20, as described above, in additional combination with other biologically active ingredients and non-drug therapies (for example, surgery or radiation treatment). When combinatorial therapy further comprises drug-free treatment, drug-free treatment can be conducted at any suitable time, provided that a beneficial effect of the combined action of the combination of therapeutic agents and drug-free treatment is obtained. For example, in suitable cases, the beneficial effect is still obtained, when the drug-free treatment is temporarily removed from the administration of the therapeutic agent, perhaps for days or even weeks.

The α-aminoamide compositions of the invention can be administered in a variety of dosage forms, for example, orally, in the form of tablets, troches, capsules, sugar or film coated tablets, liquid solutions, emulsions or suspensions; rectal-

·· *, in the form of suppositories; parenterally, for example, by intramuscular or intravenous injection or infusion; and transdermally in the form of * a plaster, ointment, emulsion, lotion, solution, gel, cream and nasal spray.

- Suitable organic and / or inorganic vehicle and / or therapeutically inert, pharmaceutically acceptable excipient materials useful in the preparation of such a composition, include, for example, water, gelatin, acacia, lactose, starch, cellulose, magnesium stearate, talc, vegetable oils, cyclodextrins, poly (alkylene glycols) and the like. The aaminoamide compositions of formula (I) can be sterilized and can contain other components, well known to those skilled in the art, such as, for example, preservatives, stabilizers, humectants or emulsifiers, for example, paraffinic oil, mannitol monooleate, salts to adjust osmotic pressure, buffers and the like.

In addition, the solid oral forms may contain, together with the active agent, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearate, and / or poly (ethylene glycols); binding agents, for example, starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; agents

20 · disintegrators, for example, a starch, alginic acid, alginates or sodium glycolate and starch, effervescent mixtures; dyestuffs; sweeteners; humectants such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Pharmaceutical preparations can be produced in any known manner, for example, by means of mixing, granulating, tabletting, sugar coating or film coating processes.

Oral formulations comprise sustained release formulations, which can be prepared in a conventional manner, for example, by applying an enteric coating to tablets and granules.

The liquid dispersion for oral administration can be, for example, syrups, emulsions and suspensions. Syrups may also contain as a vehicle, for example, sucrose or sucrose with glycerin and / or mannitol • and / or sorbitol.

• Suspensions and emulsions may contain as a vehicle, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or poly (vinyl alcohol). Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, ethyl oleate, glycols, for example, propylene glycol, and, if desired, an adequate proportion of lidocaine hydrochloride . Solutions for intravenous injections or infusions may contain as a vehicle, for example, sterile water or preferably they may be in the form of sterile, aqueous or isotonic saline solutions.

Suppositories may contain, together with the active agent, a pharmaceutically active carrier, for example, cocoa butter, poly (ethylene glycol), a polyoxyethylene sorbitan fatty acid ester surfactant, or lecithin.

Compositions including α-aminoamides of formula (I) are generally in the form of a unit dose, containing, for example, 20 to 7,000 mg of active ingredient per unit dosage form. Adequate treatment is given 1 or 2 or 3 times a day, depending on the release rate. Consequently, the desired dose can be presented in a single dose or as divided doses administered at appropriate intervals, for example, two to four or more sub-doses per day.

Pharmaceutical compositions, including an α-aminoamide of formula (I), can contain, by unit dosage, for example, capsule, tablet, powder, injection, measuring spoon, suppository and the like, from about 20 to 7,000 mg of the agent active.

The optimal therapeutically effective doses to be administered can be easily determined by those skilled in the art and will vary, basically, with the concentration of the preparation, with the mode of administration and with the progression of lower urinary tract disorders.

tated. In addition, factors associated with the particular patient being treated, including age, weight, patient's diet and time of administration * to the patient, will result in the need to adjust the dose to an appropriate therapeutically effective level.

The advantages derived from the uses and methods of the invention, as defined above, are many and include the possibility of preventing and treating basically all types of lower urinary tract disorders.

The effect of a representative compound of formula I, (0) - (+) - 2 [4- (2-fluorobenzyloxy) -benzylamino] -propanamide (NW-1029), in the function of urine elimination, was tested in the models of rats presented below of Acute acid bladder irritation and cyclophosphamide (CYP) intermediate bladder irritation.

Continuous infusion cystometrograms (0.04 mL / min) were used to measure the intervals between contractions (ICIs), which provide an estimate of bladder capacity. Response curves to cumulative doses were obtained in each animal by administering increasing intravenous doses of the drug.

Acute irritation of the bladder by acetic acid in rats

Procedure:

The experiments were conducted using adult anesthetized female Sprague Dawley rats (170 - 200 g).

A catheter (PE-50) was inserted through an abdominal incision in an intermediate line in the bladder through the upper part of the bladder, and then the intravesical pressure was measured to monitor the bladder activity, 25 during a continuous infusion of 0.15% of Acetic Acid. The intervals between contractions (ICIs), the maximum contraction pressure and the pressure limits inducing contraction of bladder reflex were measured before and after intravesical infusion of acetic acid in rats treated with NW-1029.

Results:

The continuous intravesical infusion of acetic acid (AA) irritates the bladder and reduces ICI in anesthetized rats. NW-1029 (3, 10 and 30 mg / kg) produces a significant reversal of the AA-induced reduction in ICI in rats · «··· * ··« «· · · * #

·· * ·· »«

. «· · * • * « • ·· t · * ♦ • » · ·· • ··

anesthetized (figure 1).

Intermediate irritation of the bladder by cyclophosphamide (CYP) in rats

The experiments were conducted using both waking and anesthetized adult female S5 plague Dawley rats (170 - 200 g).

Chemical cystitis was induced by CYP, which is metabolized to acrolein, an irritant eliminated in the urine. CYP (150 mg / kg / ip - intraperitoneal) was administered one day before the experiment.

NW-1029 was administered in a dose range of 0.1 to 10 mg / kg / iv - intravesical.

Results;

Pretreatment with CYP causes bladder irritation and very frequent urine flushes, with an ICI of around 150 - 200 seconds between urine flushes. The administration of NW-1029, in a dose range of 0.1 to 10 mg / kg / iv significantly increases the ICI in both awake and anesthetized rats (figures 2 and 3).

The examples presented below are presented to more fully illustrate preferred embodiments of the invention.

EXAMPLE 1

2-í (3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino1-N-methylpropanamide

To a solution of N-methylalaninamide hydrochloride (0.50 g, 3.61 mmoles) in methanol (10 mL), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.36 g, 5, 69 mmoles) and a solution of 3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-carboxaldehyde (0.90 g, 3.61 mmoles) in 25 methanol (10 ml) was added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate / methanol = 98/2) yielding 0.93 g of the title compound (77% yield).

¹ H-NMR (200 MHz, CDCI ₃ ); Δ: 1.30 (d. 3H, J = 6.8 Hz); 1.76-2.19 (m, 2H); 2.64-2.87 (complex, 6H, J = 7.7 Hz); 3.29 (q, 1H, J = 7.0 Hz); 3,353.50 (m, 1H); 3.66 (s, 2H); 4.19-4.26 (m, 1H); 4.57-4.66 (dd, 1H, J = 9.2 Hz);

6.72 (d, 1H, J = 8.2 Hz); 7.01-7.32 (complex, 7H).

¹³ C-NMR (200 MHz.CDCIs); δ: 19.5; 25.9; 33.5; 36.6; 41.4; 52.3; 57.6; 77.0; 109.4; 124.4; 126.1; 128.4; 128.5; 130.8; 131.3; 141.4; 159.5; 175.0.

Similarly, the following compounds have also been synthesized,

2 - [(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -propanamide; 2- {3- [2- (2-Fluorophenetit)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) -propanamide; 2-3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) -Nomethylpropanamide;

2- {3- [2- (3 "Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2- {3- [2- (3-Chlorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) 15 N-methylpropanamide;

2 - [(3-Phenethyl-2,3-dihydrobenzopyran-6-ylmethyl) -amino] - propanamide;

2 - [(4-Phenethyl-2,3-dihydrobenzoxepin-7-ylmethyl) -amino] - propanamide;

2 - [(3-Phenethyl-2,3-dihydrobenzothiophen-5-ylmethyl) -amino] - propanamide;

2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide;

2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-methylmethyl} -amino) 25 propanamide; and 2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) N-methylpropanamide.

2 - [(3-Benzyl-2 ₃ 3-dihydrobenzofuran-5-ylmethyl) -aminol-JN2TOtjlnroBanamide

To a solution of (S) -methylalanamide hydrochloride (0.50 g, 3.6 mmoles) in methanol (10 mL), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.44 g, 6.9 mmoles) and a solution of 3-benzyl19

at

2,3-dihydro-1-benzofuran-5-carbaldehyde (0.75 g, 3.6 mmoles) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate) yielding 0.58 g of the title compound (50% yield).

¹ H-NMR (400 MHz.CDCh); δ: 1.32 (d, 3H, J = 6.9 Hz); 2.83-2.91 (m, 4H); 3.05 (dd, J = 2.4, 6.5 Hz, 1H); 3.26 (q, 1H, J = 7.0 Hz); 3.62 (s, 2H); 3.73-3.76 (m, 1H); 4.32 (dd, 1H, J = 5.7, 8.9 Hz); 4.55 (t, 1Η, J = 9.0 Hz);

6.76 (d, 1H, J = 8.1 Hz); 6.86 (bs, 1H), 7.07 (d, 1H, J = 8.1 Hz); 7.27-7. 36 (m,

5H).

¹³ C-NMR (400 MHz.CDCh); δ: 19.72; 25.84; 41.04; 43.39; 52.29; 57.55; 109.42; 124.49; 126.51; 128.35; 128.53; 129.05; 130, 68; 131.16; 139.06; 159.36; 175.37.

2 - [(3-Benzyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -propanamide;

2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) N-methylpropanamide;

2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide;

2-3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) -Nmethylpropanamide;

2 - [(3-Benzyl-2,3-dihydrobenzothiophen-5-ylmethyl) -amino] - propanami25 da;

2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydro-benzothiophen-5-ylmethyl} amine) propanamide; and

2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide.

EXAMPLES 3 - 6: PREPARING INTERMEDIARIES

EXAMPLE 3

3- (2-Phenylethyl) -2.3-dihydro-1-benzofuran-5-carbaldehyde

· ♦ · «

To a suspension of PCC (3.69 g, 17.10 mmoles) in methylene chloride (20 mL), a solution of 3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-ylmethanol ( 3.32 g, 13.16 mmoles) in methylene chloride (100 ml) was added at room temperature. After stirring for 12 h, diethyl ether (300 ml) was added and the black solid precipitate was filtered and washed with diethyl ether many times. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 95 / 5-9 / 1), producing 0.202 of the title compound (67% yield).

1 H-NMR (200 MHz, CDCI ₃ ); δ: 1.85-2.19 (m, 2H); 2.70 (dd, 2H, J 10 = 7.8 Hz); 3.44-3.56 (m, 1H); 4.33 (dd, 1H, J = 6.6, 9.2 Hz); 4.72 (dd, 1H, J =

9.2 Hz); 6.86 (d, 1H, J = 8, 2 Hz); 7.10-7.34 (m, 5H); 7.63-7.69 (m, 2H); 7.72-7.73 (m, 1H); 9.82 (s, 1H).

Similarly, starting from 3-benzyl-2,3-dihydro-1-benzofuran-5ylmethanol, 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxaldehyde was obtained in 85% yield.

¹ H-NMR (200 MHz, CDGI ₃ ); & 1.17 (t, 3H, J = 7.1 Hz); 2.77 (dd,

1H, J = 13.8, 9.4 Hz); 3.01 (dd, 1H, J = 13.9, 5.9 Hz); 3.68-3.75 (m, 1H); 4.32 (dd, J = 9.1, 5.9 Hz, 1H); 4.56 (t, J = 9.1 Hz, 2H); 6.78 (d, 1H, J = 8.3 Hz); 7.077.24 (m, 5H); 7.45 (bs, 1H), 7.61 (dd, 1Η, J = 8.1,1.5 Hz); 9.71 (s, 1H).

EXAMPLE 4

3- (2-Phenethyl) -2.3-dihydro-1-benzofuran-5-yl-methanol

To a solution of ethyl 3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-carboxylate (4.78 g, 1.613 mmol) in toluene (160 mL), a 1.5 solution

M DIBAL in toluene (25 ml, 35.48 mmoles) was added at -30 ° C. The reaction mixture was kept under stirring and an argon atmosphere at the same temperature for 30 minutes. Then, 3 N HCI (100 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the collected organic layers were washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was removed with a rotary evaporator. The crude product (4.05 g, 99% yield) was used in the previous step without any further purification.

• «· *» ·

¹ H-NMR (200 MHz.CDCh); δ: 1.66 (bs, 1H); 1.75-2.21 (m, 2H);

2.70 (dd, 2H, J = 7.6 Hz); 3.37-3.51 (m, 1H); 4.23 (dd, 1H, J = 6.6, 9.0 Hz); 4.58 (s, 2H); 4.63 (dd, 1H, J = 8.8 Hz); 6.74 (d, 1H, J = 8.2 Hz); 7.07-7.33 (m,

7H).

¹³ C-NMR (200 MHz.CDCh); 6: 33.4; 36.5; 41.4; 65.4; 77.0;

109.4; 123.7; 126.1; 127.7; 128.3; 128.5; 131.2; 131.1; 141.4; 159.7.

Similarly, starting from ethyl 3-benzyl-2,3-dihydro-1-benzofuran-5carboxylate. 3-benzyl-2,3-dihydro-1-benzofuran-5-yl-methanol was obtained in a 62% yield.

¹ H-NMR (200 MHz.CDCh); δ: 1.18 (t, 3H, J = 7.2 Hz); 2.74 (dd,

1H. J = 13.8, 9.3 Hz); 3.00 (dd, 1H, J = 13.8, 6.1 Hz); 3.61 - 3.70 (m, 1H); 4.21 (dd, 1H, J = 8.9, 5.9 Hz); 4.50 (m, 3H); 6.68 (d, 1H, J = 8.1 Hz): 6.93 (d, J = 0.5 Hz, 1H); 7.01-7.24 (m, 6H).

EXAMPLE 5

Ethyl 3- (2-Phenylethyl) -2,3-dihydro-1-benzofuran-5-carboxylate

To a solution of ethyl 3-iodo-4 - {[(2E) -4-phenylbut-2-enyl] -oxy} benzoate (13.42 g, 31.73 mmol) and AIBN (0.52 g, 3 , 17 mmoles) in benzene (900 ml), tributyltin hydride (12 ml, 44.43 moles) was added at room temperature and the reaction mixture was heated to reflux. After 2 hr, the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 95/5) yielding 9.14 g of the title compound (97% yield).

¹ H-NMR (200 MHz.CDCh); δ: 1.36 (t, 3H, J = 7.5 Hz); 1.80-2.26 (m, 2H); 2.67 (dd, 2H, J = 7.8 Hz); 3.39-3.54 (m, 1H); 4.27-4.34 (m, 3H); 4.69 25 (dd, 1H, J = 9.0 Hz); 6.77 (d, 1H, J = 7.4 Hz); 7.16-7.32 (m, 5H); 7.85-7.90 (m, 2H).

¹³ C-NMR (200 MHz.CDCh); δ: 14.4; 33.3; 36.6; 40.8; 60.6; 77.7; 109.2; 123.7; 126.1; 128.4; 128.5; 131.2; 141.2; 163.1; 166.5.

Similarly, starting from ethyl 3-iodo-4 - [(2E) -3-phenylprop-2-enyl] 30 oxybenzoate, ethyl 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate to a 90% yield.

¹ H-NMR (200 MHz.CDCh); δ: 1.27 (t, 3H, J = 7.1 Hz); 2.74 (dd,

1H, J = 13.8, 9.4 Hz); 3.03 (dd, 1H, J = 13.9, 5.9 Hz); 3.65-3.73 (m. 3H); 4,184.32 (m, 1H); 4.50 (t, J = 9.1 Hz, 2H); 6.70 (d, 1H, J = 8.3 Hz): 7.07-7.24 (m, 5H); 7.63 (bs, 1H), 7.81 (dd, 1H, J = 8.1, 1.5 Hz).

EXAMPLE 6

Ethyl 3-sludge-4- (f (2E) -4-phenylbut-2-enyl] oxy} -benzoate

To a suspension of NaH (0.82 g, 20.5 mmoles) in THF (40 mL), a solution of ethyl 4-hydroxy-3-iodobenzoate (5.0 g, 17.1 mmoles) in THF (40 ml), then 15-crown-5 (4.0 ml, 25.6 mmoles) and finally a solution of 4-phenylbut-2-enyl bromide (5.41 g, 25.6 mmoles) in THF 10 (50 mL) were subsequently added at 0 ° C. The reaction mixture was kept under stirring at room temperature for 10 minutes and then heated to 50 ° C for 6 h. After equilibration at room temperature, 3 N HCI (30 mL) was added and the mixture poured into a separatory funnel. The organic layer was separated and the aqueous layer extracted with 15 ethyl acetate (3 x 30 ml). The collected organic layers were washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was removed with a rotary evaporator. The residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 95/5), yielding 5.94 g of the title compound (82% yield).

¹ H-NMR (200 MHz, CDCI ₃ ); δ: 1.36 (t, 3H, J = 7.2 Hz): 3.43 (d, 2H,

J = 6.6 Hz); 4.33 (q, 2H, J = 7.2 Hz); 4.61 (dd, 2H, J = 1.2, 5.6 Hz); 5.67-6.15 (m, 2H); 6.78 (d, 1H, J = 8.6 Hz); 7.15-7.30 (m, 5H); 7.96 (dd, 1H, J = 2.0, 8.6 Hz); 8.44 (d, 1H, J = 2.0 Hz).

¹³ C-NMR (200 MHz, CDCI ₃ ); Õ: 14.4; 38.7; 61.0; 69.6; 111.3; 25 125.1; 126.3; 128.5; 131.4; 134.1; 141.0.

Similarly, starting with ethyl bromide and cinnamyl, 3-iodine-

Ethyl 4 - {[(2E) -3-phenylprop-2-enyl] -oxy} -benzoate was obtained in 72% yield.

1 H-NMR (200 MHz.CDCh); δ; 1.28 (t, 3H, J = 7.1 Hz); 4.24 (q,

2H, J = 7.1 Hz); 4.69 (dd, 2H, J = 1.5-5.4 Hz); 6.24-6.35 (m, 1H), 6.68-6.76 (m, 2H); 7.16-7.34 (m, 5H); 7.90 (dd, 1H, J = 2.0, 8.6 Hz); 8.38 (d, 1H, J = 1.8 Hz).

Claims (4)

claims 1. Compound of α-aminoamide, characterized by the fact that it has the formula (I) in which: - R is a furyl, thienyl or pyridyl ring, or a phenyl ring optionally substituted by one or two substituents selected independently from halogen, hydroxy, cyano, C1 - C6 alkyl, C1 - C6 alkoxy or trifluoromethyl; - R1 is hydrogen or C1 - C6 alkyl or C3 - C7 cycloalkyl; - R2 and R3 are selected independently of hydrogen, C1 - C4 alkyl optionally substituted by hydroxy or phenyl, phenyl, the phenyl rings being optionally substituted by one or two substituents selected independently from C1 - C6 alkyl, halogen, hydroxy, C1 C6 alkoxy or trifluoromethyl; or R2 and R3, considered with the carbon atom to which they are attached, form a C3 - C6 cycloalkyl ring; - R4 and R5 are, independently, hydrogen, C1 - C6 alkyl or C3 - C7 cycloalkyl; or R4 and R5, taken together with the nitrogen atom to which they are attached, form a pyrrolidine or piperidine ring; - X is CH2, O or S; - Y and Z taken together form a dihydrobenzofuran or dihydrobenzothiophene or dihydrobenzo (thio) pyran or tetrahydrobenzo (thio) oxepine heterocycle; or racemic mixtures, mixtures and pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized by the fact that it is selected from: 2 - [(3-Benzyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] - propanamide; 2 - [(3-Benzyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -Nmethylpropanamide; Petition 870190048027, of 05/22/2019, p. 4/10 (2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide; 2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) N-methylpropanamide; 5 2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide; 2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) N-methylpropanamide; 2 - [(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] 10 propanamide; 2 - [(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl) -amino] -Nmethylpropanamide; 2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide; 15 2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) N-methylpropanamide; 2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} -amino) propanamide; 2- {3- [2- (3-Chlorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl} - amino) 20 propanamide; 2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzofuran-5-ylmethyl amino) -Nmethylpropanamide; 2 - [(3-Phenethyl-2,3-dihydrobenzopyran-6-ylmethyl) -amino] propanamide; 2 - [(4-Phenethyl-2,3-dihydrobenzoxepin-7-ylmethyl) -amino] propanamide; 2 - [(3-Benzyl-2,3-dihydrobenzothiophen-5-ylmethyl) -amino] - propanamide; 2- {3- [2- (2-Fluorobenzyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide; 30 2- {3- [2- (3-Fluorobenzyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide; 2 - [(3-Phenethyl-2,3-dihydrobenzothiophen-5-ylmethyl) -amino] Petition 870190048027, of 5/22/2019, p. 5/10 propanamide; 2- {3- [2- (2-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide; 2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) propanamide; and 2- {3- [2- (3-Fluorophenethyl)] - 2,3-dihydrobenzothiophen-5-ylmethyl} -amino) N-methylpropanamide; or racemic mixtures, mixtures and pharmaceutically acceptable salts thereof. 3. Pharmaceutical composition, characterized by the fact that it comprises a pharmaceutically acceptable excipient and, as an active agent, an effective amount of a compound as defined in claim 1 or 2. 4. Use of a compound as defined in claim 1 or 2, characterized in that it is in the preparation of a medicine for the treatment of lower urinary tract disorders selected from bladder overactivity (OAB), prostatitis and prostadinia, interstitial cystitis, hyperplasia benign prostatic and urinary incontinence.